Multidomain intervention for the prevention of cognitive decline after stroke - a pooled patient-level data analysis.

BACKGROUND AND PURPOSE: The aim of this pooled patient-level data analysis was to test if multidomain interventions, addressing several modifiable vascular risk factors simultaneously, are more effective than usual post-stroke care for the prevention of cognitive decline after stroke. METHODS: This pooled patient-level data analysis included two randomized controlled trials using a multidomain approach to target vascular risk factors in stroke patients and cognition as primary outcome. Changes from baseline to 12 months in the trail making test (TMT)-A, TMT-B and 10-words test were analysed using stepwise backward linear mixed models with study as random factor. Two analyses were based on the intention-to-treat (ITT) principle using different imputation approaches and one was based on complete cases. RESULTS: Data from 322 patients (157 assigned to multidomain intervention and 165 to standard care) were analysed. Differences between randomization groups for TMT-A scores were found in one ITT model (P = 0.014) and approached significance in the second ITT model (P = 0.087) and for complete cases (P = 0.091). No significant intervention effects were found for any of the other cognitive variables. CONCLUSION: We found indications that multidomain interventions compared with standard care can improve the scores in TMT-A at 1 year after stroke but not those for TMT-B or the 10-words test. These results have to be interpreted with caution due to the small number of patients.

Whole brain MP2RAGE-based mapping of the longitudinal relaxation time at 9.4T.

Mapping of the longitudinal relaxation time (T1) with high accuracy and precision is central for neuroscientific and clinical research, since it opens up the possibility to obtain accurate brain tissue segmentation and gain myelin-related information. An ideal, quantitative method should enable whole brain coverage within a limited scan time yet allow for detailed sampling with sub-millimeter voxel sizes. The use of ultra-high magnetic fields is well suited for this purpose, however the inhomogeneous transmit field potentially hampers its use. In the present work, we conducted whole brain T1 mapping based on the MP2RAGE sequence at 9.4T and explored potential pitfalls for automated tissue classification compared with 3T. Data accuracy and T2-dependent variation of the adiabatic inversion efficiency were investigated by single slice T1 mapping with inversion recovery EPI measurements, quantitative T2 mapping using multi-echo techniques and simulations of the Bloch equations. We found that the prominent spatial variation of the transmit field at 9.4T (yielding flip angles between 20% and 180% of nominal values) profoundly affected the result of image segmentation and T1 mapping. These effects could be mitigated by correcting for both flip angle and inversion efficiency deviations. Based on the corrected T1 maps, new, 'flattened', MP2RAGE contrast images were generated, that were no longer affected by variations of the transmit field. Unlike the uncorrected MP2RAGE contrast images acquired at 9.4T, these flattened images yielded image segmentations comparable to 3T, making bias-field correction prior to image segmentation and tissue classification unnecessary. In terms of the T1 estimates at high field, the proposed correction methods resulted in an improved precision, with test-retest variability below 1% and a coefficient-of-variation across 25 subjects below 3%.

Non-infectious risk factors for different types of cerebral palsy in term-born babies: a population-based, case-control study.

OBJECTIVE: To identify non-infectious antenatal and perinatal risk factors for cerebral palsy (CP) and its subtypes in children born at term. DESIGN: A population-based, case-control study. SETTING: The western healthcare region of Sweden. POPULATION: A population-based series of children with CP born at term during 1983-94 (n=309) was matched with a control group (n=618). METHODS: A total of 62 variables, maternal characteristics, and prepartal, intrapartal and postpartal variables were retrieved from obstetric records. Both univariate and multivariate analyses were performed for spastic and dyskinetic CP, and for the total CP group. MAIN OUTCOME MEASURES: Cerebral palsy (CP) and subtypes. RESULTS: Univariate analysis resulted in 26 significant risk factors for CP. Birthweight (OR 0.54, 95% CI 0.39-0.74), not living with the baby's father (OR 2.58, 95% CI 1.11-5.97), admittance to a neonatal intensive care unit (NICU) (OR 4.43, 95% CI 3.03-6.47), maternal weight at 34 weeks of gestation (OR 1.02, 95% CI 1.00-1.03) and neonatal encephalopathy (OR 69.2, 95% CI 9.36-511.89) were found to be risk factors for CP in the total CP group in our multivariate analysis. Factors during the periods before, during and after delivery were all shown to increase the risk of spastic diplegia and tetraplegia, whereas mostly factors during the period before delivery increased the risk of spastic hemiplegia, and only factors during delivery increased the risk of dyskinetic CP. Admittance to an NICU was a risk factor for all CP subtypes. CONCLUSIONS: The risk factor pattern differed by CP subtype. The presented risk factors may be useful indicators for identifying children at risk of developing CP, and helpful for targeting individuals for early intervention programmes.

The changing panorama of cerebral palsy in Sweden. X. Prevalence and origin in the birth-year period 1999-2002.

AIM: The aim of the study was to describe the prevalence and origin of cerebral palsy (CP), which is the tenth report from the western Swedish study. METHODS: A population-based study covering 85,737 live births in the area in 1999-2002. Birth characteristics and neuroimaging findings were recorded, prevalence of CP was calculated and aetiology was analysed. RESULTS: CP was found in 186 children. The crude prevalence was 2.18 per 1000 live births. The gestational age-specific prevalence for <28 gestational weeks was 55.6 per 1000 live births, whereas it was 43.7 for 28-31 weeks, 6.1 for 32-36 weeks and 1.43 per 1000 for >36 weeks. There was a female majority among children born at term and a male predominance in children born preterm. Hemiplegia accounted for 38%, diplegia for 32%, tetraplegia for 7%, whereas 17% had dyskinetic CP and 5% ataxia. Neuroimaging showed white-matter lesions in 31% and cortical/subcortical lesions in 29%. The aetiology was considered to be prenatal in 36%, peri/neonatal in 42%, whereas it remained unclassified in 21%. CONCLUSION: The decrease in CP prevalence observed since the 1980s had ceased. An increase in children born at term and in dyskinetic CP was found. In children born before 28 weeks of gestation, the prevalence decreased significantly. White-matter and cortical/subcortical lesions dominated on neuroimaging.

Cerebral palsy and restricted growth status at birth: population-based case-control study.

OBJECTIVE: To evaluate the association between growth status at birth and subsequent development of cerebral palsy in preterm and term infants. DESIGN: Population-based case-controlled study. SETTING: Cerebral palsy register in Western Sweden. Subjects Cohort of 334 singletons born between 1983 and 1990, with cerebral palsy diagnosed from age 4, and 668 singletons matched for gestation, gender and delivery unit. METHOD: Growth status at birth was determined using small for gestational age (SGA) categories, with customised birthweight percentiles (SGAcust) based on the Swedish population. MAIN OUTCOME MEASURES: Proportion of babies that were SGAcust, comparing cases and controls in three gestational age categories: early preterm (24-33 weeks), late preterm (34-36 weeks) and term (37+ weeks). RESULTS: Of the 334 children with cerebral palsy, 87 (26.6%) were born early preterm, 27 (8.1%) late preterm and 218 (66%) at term. Children who had been born at term were more likely to have been SGA <1st customised percentile (SGAcust1) than their matched controls (OR 6.6, 95% CI 2.3-18.6). In contrast, children with cerebral palsy born preterm were not more likely to have been SGAcust1 (OR 0.9, 95% CI 0.4-1.9), and this applied to early preterm as well as late preterm births. For less severely small babies (SGA between 1st and 5th customised percentiles), the association with cerebral palsy remained significant for term births (OR 5.2, 95% CI 2.7-10.1) but was again not significant for preterm births. CONCLUSIONS: Term singletons with severely SGA birthweights had a five- to seven-fold risk of developing cerebral palsy compared with gestational age-matched infants with birthweights within normal limits. For children born preterm, SGA was not more likely to be present in cases than in controls. These findings support the concept of cerebral palsy as a multifactorial condition and highlight the importance of antenatal surveillance of fetal growth.

Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(beta-11C) DOPA and PET.

BACKGROUND: The aim of the present study was to investigate dopamine synthesis in the brain of drug-free schizophrenic patients, not only in the striatum but also in extrastriatal areas like the prefrontal cortex, brain areas that for a long time has been in focus of interest in the pathophysiology of schizophrenia. METHODS: PET was performed in 12 drug-free (10 drug-naive) psychotic schizophrenic patients and 10 healthy volunteers matched for age and gender using 11C-labelled L-DOPA as the tracer. The time-radioactivity curve from occipital cortex (located within Brodman area 17 and 18) was used as input function to calculate L-DOPA influx rate, Ki images, that were matched to a common brain atlas. A significant overall increase of the Ki values was found in the schizophrenic group as compared with healthy controls. RESULTS: In particular, significantly higher Ki were found in the schizophrenic patients compared to the controls in the caudate nucleus, putamen and in parts of medial prefrontal cortex (Brod 24). The Ki value reflect an increased utilization of L-DOPA, presumably due to increased activity of the amino acid decarboxylate enzyme. CONCLUSIONS: The results indicate that the synthesis of dopamine is elevated within the striatum and parts of medial prefrontal cortex in schizophrenia.

Stimulation of 5-HT2A receptors on astrocytes in primary culture opens voltage-independent Ca2+ channels.

Mechanisms underlying the 5-HT2A receptor induction of intracellular Ca2+ mobilization and Ca2+ influx in type I astroglial cells in primary culture from newborn rat cerebral cortex were evaluated. The 5-HT-evoked Ca(2+)-transients, inhibited by the 5-HT2A antagonists ketanserin or 4-(4-fluorobenzoyl)-1-(4-phenylbutyl) piperidine oxalate, consisted of an initial peak caused by inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ release from internal stores, and a second sustained part which was due to Ca2+ transport over the plasma membrane. The responses were pertussis toxin-insensitive, suppressed by the phospholipase C inhibitor neomycin and were inhibited by the Ca(2+)-ATPase inhibitor thapsigargin. Furthermore, the responses were inhibited by the IP3 receptor antagonist heparin. When the second sustained part of the 5-HT-evoked response was studied, it was concluded that Ca2+ influx was not a result of opening of voltage operated calcium channels of either L, N or T-type. Instead it appeared that Ca2+ entered the cells through specialized voltage independent Ca2+ channels which were dependent of the IP3 production and subsequent Ca2+ release from internal stores. From this, we conclude that 5-HT opens Ca2+ channels in astrocytes which closely resemble depletion-operated Ca2+ channels (DOCCs).

Serial proton MR spectroscopy of contrast-enhancing multiple sclerosis plaques: absolute metabolic values over 2 years during a clinical pharmacological study.

BACKGROUND AND PURPOSE: The time courses of total creatine (Cr), N-acetylaspartate (NAA), choline (Cho), and myo-inositol have not previously been investigated in the follow-up of contrast-enhancing multiple sclerosis (MS) plaques. Therefore, over a period of 2 years, we compared the absolute concentrations of these metabolites between patients treated with a placebo or 15 +/- deoxyspergualin (DSG) and between clinical groups with relapsing-remitting or secondary-progressive MS. METHODS: Sixteen patients, recruited from a pharmacological study of DSG, and 11 healthy control subjects were investigated by a stimulated-echo acquisition mode sequence (TR/TE = 3000/20). The selected volume initially contained a contrast-enhancing plaque, which was followed up for a period of 2 years. RESULTS: In contrast-enhancing plaques, Cho was significantly elevated and showed a significant reduction after both 3 and 12 months. The initially normal Cr significantly increased between 3 and 12 months, and was negatively correlated with plaque volume on T1-weighted MR images. NAA initially showed normal values, a significant decrease at 1 month, and a slow recovery over 2 years. Myo-inositol did not show a clear tendency. The placebo group did not differ from the treated group, nor did the relapsing-remitting group differ from the secondary-progressive group. CONCLUSION: The contradictory time courses of Cr and NAA show that an absolute quantification in proton MR spectroscopy in MS is necessary to avoid a false interpretation of reduced NAA/Cr ratios. The increase in Cr is probably due to remyelination. The initial dip and later recovery of NAA seem to be related to diminishing edema and remyelination.

Cerebral hemodynamics in asymptomatic patients with internal carotid artery occlusion: a dynamic susceptibility contrast MR and transcranial Doppler study.

BACKGROUND AND PURPOSE: Perfusion imaging with dynamic susceptibility contrast MR imaging (DSC-MRI) has been used to evaluate hemodynamic status in patients with symptomatic occlusive cerebrovascular disease. The aim of the present study was to determine the hemodynamic changes occurring in asymptomatic patients with unilateral internal carotid artery (ICA) occlusion by use of DSC-MRI with transcranial Doppler (TCD) measurement of the breath-holding index (BHI). METHODS: Nine patients with asymptomatic unilateral ICA occlusion underwent DSC-MRI and TCD examination. One patient was excluded from final analysis because of severe movement artifacts. On a separate workstation, regional cerebral blood volume (rCBV), regional cerebral blood flow (rCBF), and regional mean time to peak (rMTT) were calculated on the basis of signal decay rate during the passage of gadolinium bolus through the sampled volume in the territory of the middle cerebral artery. TCD-BHI was calculated in all patients. Six healthy subjects underwent the same MR protocol as the patients. RESULTS: Compared with control subjects, patients with unilateral ICA occlusions had hemodynamic changes in the ipsilateral hemisphere: rCBF was significantly lower than in controls (P <.01), and r MTT was significantly increased in both white (WM) and gray matter (GM) in the affected side (WM: P <.01; GM: P <.05). No statistically significant difference in rCBV was found in the group of patients (occluded versus contralateral, P <.1) or between the patient and control groups (occluded side versus controls, P <.1). The correlation of rCBV and BHI showed a strong relation of the two variables, showing a decrease of the latter when the former increased. CONCLUSION: DSC-MRI is a valuable tool for measuring hemodynamic changes in the presence of carotid disease with hemodynamic impairment. In our opinion, hemodynamic changes and efficiency of collateral pathways can be evaluated in occlusive carotid disease by using paired measurement of BHI and DSC-MRI. In the patient group, MR-determined rCBV and TCD-determined BHI showed a significant inverse correlation, suggesting similar significance of the two indices.

Recurrences after initial dislocation of the shoulder. Results of a prospective study of treatment.

During the years 1978 and 1979, the results in 257 patients with a primary anterior dislocation of the shoulder were prospectively studied. The patients were less than forty years old and had been treated at twenty-seven Swedish hospitals. Thirty-two patients had a fracture of the greater tuberosity, but none of them reported having any further dislocations within two years after treatment, while 32 per cent of the patients without this fracture had a redislocation during the same period. The incidence of fractures of the greater tuberosity varied with the age of the patient; the highest rates were in the age groups of twelve to thirteen years and thirty-four to forty years (43 and 30 per cent, respectively), while in the age group of twenty to twenty-two years this injury was found in only 3 per cent of the patients. Chip fractures of the glenoid rim were found in 8 per cent of the patients, most of whom were in the older age groups. Impression fractures in the posterior part of the humeral head were demonstrated in 55 per cent of the patients and were not associated with a significantly higher rate of recurrence of dislocation. One hundred and twelve patients used an immobilization device for three to four weeks, while 104 patients began to use the shoulder as early and as freely as possible. At the two-year follow-up the groups showed an equal rate of recurrence of dislocation. In the age group of twenty-two years or younger nearly 50 per cent of the patients had one or more recurrences, regardless of treatment. In the two older age groups (twenty-three to twenty-nine and thirty to forty years old), the incidence of recurrence was 25 per cent or less.

Infantile hydrocephalus epidemiology: an indicator of enhanced survival.

The epidemiology of infantile hydrocephalus in the birth years 1973-90 was investigated in west Sweden. The study revealed a significant increase in prevalence from 1973-8 and 1979-82 considered due to the enhanced survival of very and extremely preterm infants. The increase did not continue from 1983-90. This could indicate an improved outcome in preterm survivors as the neonatal survival rate continued to increase. The striking predominance of a perinatal/neonatal aetiology in very preterm hydrocephalic infants could be confirmed: 89% born from 1983-90 had suffered a confirmed postpartum intraventricular haemorrhage. In infants born at term, prenatal origins, mainly maldevelopments, dominated. The outcome in very preterm surviving infants with infantile hydrocephalus was poor: 73% had cerebral palsy, 52% epilepsy, 22% severe visual disability, and 55% were mentally retarded. Despite the increased survival resulting in a majority of healthy infants, there is an accumulating cohort of hydrocephalic children.

N-[11C]methylspiperone PET, in contrast to [11C]raclopride, fails to detect D2 receptor occupancy by an atypical neuroleptic.

The occupancy of the atypical neuroleptic quetiapine (Seroquel) at the D2 dopamine receptor was investigated using the PET tracers [11C]raclopride and N-[11C]methylspiperone in a group of five schizophrenic patients. A steady-state treatment condition was ensured by dosing the patients with 750 mg quetiapine daily during 3 weeks followed by a period of tapering off the dose. For each patient, PET examinations were performed with both tracers at two of the following doses: 750, 450, 300 and/or 150 mg. As control, a group of six healthy untreated volunteers was investigated. The D2 binding potential in the putamen and the caudate nucleus was determined by using an evaluation method based on the method proposed by Patlak and Blasberg. The receptor occupancy was determined by assuming that the group of healthy volunteers is representative of untreated drug-naive schizophrenic patients. While a significant linear trend of increasing occupancy with increasing quetiapine dose (reaching 51% +/- 10% occupancy at the 750 mg dose) was detected with [11C]raclopride (P < 0.01), no such trend was apparent for N-[11C]methylspiperone (P > 0.09, maximal occupancy values were 2% +/- 3%, measured for the group of three patients on 450 mg). The study suggests that N-[11C]methylspiperone cannot be used for the assessment of D2 receptor occupancy induced by quetiapine. The result is discussed in terms of endogenous dopamine, tracer kinetics and equilibrium dissociation constants.

Intermolecular double quantum coherences (iDQc) and diffusion-weighted imaging (DWI) imaging of the human brain at 1.5 T.

To study the sensitivity of intermolecular double quantum coherences (iDQc) imaging contrast to brain microstructure and brain anisotropy, we investigated the iDQC contrast between differently structured areas of the brain according to the strength and the direction of the applied correlation gradient. Thus diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) maps have been obtained. This procedure, which consists of analyzing both iDQc and DWI images at different gradient strength and gradient direction, could be a promising tool for clinical brain investigations performed with higher than 1.5 T magnetic fields.

In vivo multiple spin echoes imaging of trabecular bone on a clinical 1.5 T MR scanner.

In vivo multiple spin echoes (MSE) images of bone marrow in trabecular bone were obtained for the first time on a clinical 1.5 T scanner. Despite of a reduced sensitivity of the MSE trabecular bone images with respect to the cerebral matter ones, it is possible to observe some features in the MSE trabecular bone images that may be useful in the diagnosis of osteopenic states. Two different CRAZED-type MSE imaging sequences based on spin-echo and EPI imaging modalities were applied in phantom and in vivo. Preliminary experimental results indicate that EPI imaging readout seems to conceal the MSE contrast correlated with pore dimension in porous media. However it is still possible to detect anisotropy effects related to the bone structure in MSE-EPI images. Some strategies are suggested to optimize the quality of MSE trabecular bone images.

The changing panorama of infantile hydrocephalus and cerebral palsy over forty years--a Swedish survey.

The time trends and background of infantile hydrocephalus (IH) and cerebral palsy (CP) are surveyed. The changes in live birth prevalence, disability patterns, associated neuroimpairments and distribution of etiologies are analysed. Both the risk of IH and that of CP sharply increase with decreasing birth weight and gestational age. It is concluded that the remarkably enhanced survival of particularly very preterm infants, those at the highest risk of long-term morbidity, implies an increasing number of impaired children as long as the outcome of survivors is not drastically improved. The data presented are thought to be of relevance as to reconsideration of the effectiveness of perinatal care for preterm babies.

Head growth in Rett syndrome.

The longitudinal development of head growth was investigated in girls with Rett syndrome (RS). Growth retardation was expressed in standard deviation (SD) scores. In classic types, the mean head circumference fell successively to 2 SD scores below the norm at the age of 4 years. After the age of 8 it stabilized close to -3 SD scores. In forme fruste variants, the mean head circumference was within normal limits; however, it was significantly below the norm, -0.8 SD scores. In girls with classic RS, head growth had decelerated by less than 1 SD score in 20% of the girls at the age of 6 years and in 10% at the age of 12 years. In forme fruste variants only a small decline in head growth occurred. Head growth decline may thus be very small in classic RS and is usually not present at all in forme fruste variants. In the future, it should, therefore, neither be regarded as a necessary diagnostic criterion for classic RS, nor as a valid one for forme fruste variants.

Arthroscopic visualization of the posteromedial compartment of the knee joint.

Introduction of the arthroscope in the midline through the patellar tendon about 1 cm. below the apex of the patella is described. The posterior compartments of the knee joint can be examined from this single entry. The technique has been used in 1232 patients without any complications. In 127 patients subjected also to arthrotomy the arthroscopic diagnosis proved to be correct in all instances except for one missed rupture of the posterior cruciate liagment. In that case a bucket handle rupture of the medial meniscus prevented the entry into the posteromedial compartment.

The changing panorama of cerebral palsy--bilateral spastic forms in particular.

Our Swedish population-based cerebral palsy (CP) project started 25 years ago and today covers the birth years 1954-1990, with over 1400 CP cases. This large series (1, 2, 3) has opened new perspectives on time trends and aetiological background factors, where two areas of successively increasing knowledge stand out as particularly helpful. One is the growing amount of biological and clinical data from the continuously increasing cohorts of surviving very preterm infants, the other is the rapidly expanding and refined information from neuroimaging. Bilateral spastic CP (BSCP), including spastic and ataxic diplegia, tetraplegia and spastic-dyskinetic CP, is the most prevalent clinical group of CP syndromes, present in around 75% of preterm and 45% of term CP, and has shown the most significant prevalence changes over time. In this presentation we, therefore, focus on BSCP, also analysed in a collaborative study between southwest Germany and western Sweden and recently presented in a series of four papers (4, 5, 6, 7).